Heart failure affects approximately three million Americans, developing at a rate of approximately 400,000 new cases per year. Current therapy for heart failure is primarily directed to using angiotensin-converting enzyme (ACE) inhibitors and diuretics. ACE inhibitors appear to slow the progression towards end-stage heart failure in patients; however, they are unable to relieve symptoms in more than 60% of heart failure patients and reduce mortality of heart failure only by approximately 15-20%. Heart transplantation is limited by the availability of donor hearts. With the exception of digoxin, the chronic administration of positive inotropic agents has not resulted in a useful drug without accompanying adverse side effects, such as increased arrhythmia, sudden death, or other deleterious side effects related to survival. These deficiencies in current therapy suggest the need for additional therapeutic approaches.
Cardiac muscle hypertrophy is one of the most important adaptive physiological responses of the myocardium. In response to increased demands for cardiac work or following a variety of pathological stimuli which lead to cardiac injury, the heart adapts through the activation of a hypertrophic response in individual cardiac muscle cells, which is characterized by an increase in myocyte size, the accumulation of contractile proteins within individual cardiac cells, the activation of embryonic gene markers expression, and the lack of a concomitant effect on muscle cell proliferation. Although the hypertrophic process can initially be compensatory, there can be a pathological transition in which the myocardium becomes dysfunctional (Braunwald (1994) in Pathophysiology of Heart Failure, (Braunwald, ed.); Saunders, Philadelphia; Vol. 14, pp 393-402).
Studies in an in vitro model system of ventricular muscle cell hypertrophy have led to the identification of a number of mechanical, hormonal, growth factor, and pathological stimuli which can activate several independent features of hypertrophy (Chien et al. (1991) FASEB J. 5:3037-3046; Knowlton et al. (1991) J. Biol. Chem. 266:7759-7768; Shubeita et al. (1990) J. Biol. Chem. 265:20555-20562; Thorburn et al. (1993) J. Biol. Chem. 268:2244-2249; LaMorte et al. (1994) J. Biol. Chem. 269:13490-13496; Knowlton et al. (1993) J. Biol. Chem. 268:15374-15380). Currently, there are at least two signal transduction pathways, involving both ras- (Thorburn et al. (1993) supra), and G.sub.q protein-dependent downstream effectors (LaMorte et al. (1994) supra) implicated in the activation of features of the hypertrophic response in the in vitro model system. While a great deal of progress has been made in uncovering the signaling pathways which activate the ventricular muscle cell hypertrophic response, relatively little is known as to the mechanisms which might inhibit or suppress the hypertrophic response.
While progress has been made in uncovering the signaling pathways which activate the ventricular muscle cell hypertrophic response, relatively little is known as to mechanisms which inhibit or suppress the hypertrophic response.
There is a need for an improved heart failure therapy, such as congestive heart failure and hypertrophic cardiomyopathy.